Clinical manifestations

Presentation and course

The typical onset of Fejerman syndrome is between 4 and 12 months of age. Affected infants usually have had normal psychomotor development prior to onset. The clinical examination remains normal. Motor manifestations usually remit spontaneously before 2 years of age without leaving any neurologic or motor sequelae (03). The types of motor phenomena in this syndrome include myoclonic spasms (which by definition are nonepileptic infantile spasms) and brief tonic contractions (with a duration of 200 or 300 msec), shuddering, and atonia or negative myoclonus (03). Additional cases with atonic episodes have been studied, including a patient with nonepileptic myoclonias in a cluster that started at the end of the second year of life. Late-onset Fejerman syndrome may also occur.

The attacks are likely to occur in clusters, sometimes recurring at frequent and brief intervals several times a day. The attacks occur more frequently while awake but may also happen during drowsiness and light sleep. The intensity of the paroxysmal motor movements varies. They are usually mild and inconspicuous but may, at times, become severe and imitate infantile spasms (29). They occur in awake states and may also be triggered by excitement, fear, anger, frustration, or the need to move the bowels or to void.

Some patients may have more than one type of nonepileptic motor manifestation in different episodes or during a single episode mainly when the seizures occur in a cluster. The latter event may be considered a nonepileptic phenomenon rather than an epileptic manifestation. Home video and video-EEG recording are important to recognize the semiological characteristics of the clinical spectrum of Fejerman syndrome.

Transient immaturity or imbalance of the serotonergic system might underlie various myoclonic phenomena, as has been postulated for benign neonatal sleep myoclonus. This could be genetic, thus, accounting for occasional familial cases of both benign neonatal sleep myoclonus and Fejerman syndrome. We evaluated four infants with self-limited focal epilepsy of infancy associated with Fejerman syndrome. These nonepileptic episodes are part of the spectrum of Fejerman syndrome and mutations in the PRRT2 gene may be involved in the etiology (25). Therefore, this particular association should be taken into account, as it may be more common than currently believed and the genetic etiology should be investigated.

Three particular cases with Fejerman syndrome were evaluated (05). Two of them were boys of 10 and 11 months of age, respectively, who had cluster events characterized in the same event by asymmetric spasms, atonic episodes, and jerks in one and spasms and shuddering episodes in the other child. We previously described infants with more than one type of motor event at different moments, but not in the same episode. The third patient was an 8-month-old female who presented with shuddering when she was crying.

The exclusion criteria are the following:

	1. Abnormal neurologic examination or neuropsychological development before onset of the clinical manifestations.
	2. Events occurring only during sleep.
	3. Events occurring as a reflex reaction to a posture or stimulus.
	4. Nonparoxysmal motor disturbances or abnormal movements lasting more than 1 minute.
	5. EEG with epileptiform interictal or ictal abnormalities.

Two infants with benign focal seizures have been evaluated (25). After starting seizures and in the first year of life, the first had nonepileptic spasms in clusters. The second had nonepileptic lateralized atonic head episodes. These two nonepileptic episodes are part of the spectrum of Fejerman syndrome, and mutations in the PRRT2 gene may be involved in the etiology.

Prognosis and complications

Fejerman syndrome or nonepileptic myoclonus of early infancy has a good prognosis with spontaneous remission in the first 4 years of life, often within months from onset and usually by the age of 2 years. Importantly, these children do not tend to have other seizure types and do not develop psychomotor deficits. Definition of the different nonepileptic paroxysmal motor disorders in infants is important for differential diagnosis, treatment, and prognosis.

Clinical vignette

A 10-month-old male with normal development started having brief shuddering attacks while awake. Two weeks later, during drowsiness, he had a brief tonic episode followed by myoclonic jerks while being breastfed. The attacks were sporadic, and the episodes did not occur in clusters. The EEG recordings were normal. Video-EEG documented that these were nonepileptic events. This patient presented with more than one type of nonepileptic motor manifestation. Parents were reassured about the good prognosis. The episodes started to improve gradually over the following 2 months and finally remitted by the age of 12 months. The patient was well at the last examination at the age of 6 years.

Biological basis

Etiology and pathogenesis

The etiology of Fejerman syndrome is unknown. Rare familial cases have been published (03).

The pathogenesis and pathophysiology of the motor manifestations in Fejerman syndrome are unknown. The events may result from an exaggeration of physiological myoclonus (27). We may also speculate that the different motor manifestations are transient episodes in an immature subcortical region.

A pathogenic role of a PRRT2 mutation in inducing benign myoclonus of early infancy or Fejerman syndrome, similar to that at the origin of other PRRT2-related paroxysmal movement disorders, such as paroxysmal kinesigenic dyskinesia, has been considered (25). We have studied two patients who started with early-onset transient movements in infancy followed by focal seizures and epileptic spasms at different moments associated with the PRRT2 gene, with excellent response to carbamazepine (unpublished data). Thus, these cases support the PRRT2 gene as a possible etiology of Fejerman syndrome. Therefore, when the clinical spectrum of Fejerman syndrome is associated with seizures, the possibility of involvement of the PRRT2 gene should be considered.

Epidemiology

The incidence and prevalence of Fejerman syndrome are not known; however, it appears to be rare. Maydell and colleagues reported only six cases collected at their institution over 10 years (27). Our group reported 59 cases over 30 years.

Differential diagnosis

Confusing conditions

The main disorder to be differentiated from Fejerman syndrome is West syndrome (15). Both are characterized by spasms occurring during infancy. A specific diagnosis cannot be made based solely on the behavioral manifestations of the spasms. However, in Fejerman syndrome the spasms do not occur as frequently, rarely involve the legs, and may have no temporal relationship to sleep. In West syndrome, the spasms usually occur on awakening. The most decisive difference is the normal ictal and interictal (including sleep) EEG and the absence of psychomotor deficits in Fejerman syndrome (11; 27; 19; 15; 31; 03; 20). Three patients with idiopathic West syndrome had nonepileptic events compatible with Fejerman Syndrome at 3.5 and 5.5 months of life, respectively, after the epileptic spams had disappeared.

Fejerman syndrome should also be differentiated from nonepileptic tonic reflex seizures described by Vigevano and Lispi (34; 33). These occur between the first and third months of life. All children have normal psychomotor development with no neurologic antecedents. The attacks are characterized by a diffuse tonic contraction with extension of all four limbs, apnea, and cyanosis lasting for 3 to 10 seconds without loss of consciousness. The attacks occur only during wakefulness and while an adult holds the child in a vertical position. They are triggered by movement or tactile stimulation. Ictal and interictal EEGs are normal. Prognosis is good with spontaneous remission within 2 months after onset (34; 33). Capovilla and colleagues described a type of nonepileptic episode characterized by repeated head drops that appeared in the second semester of the first year of life with a benign course (01). The episode could correspond to a variant of Fejerman syndrome rather than a new entity.

Fever-induced myoclonus is characterized by frequent myoclonus, which resolves with resolution of the fever in otherwise healthy children (10).

Others transient movements in normal infants characterized by more complex motor phenomena have been described by Fernandez-Alvarez as well as Piscitello and colleagues (18; 32). These authors consider these particular movements to be grouped under the same umbrella term of transient infant movements together with Fejerman syndrome; however, personally, and independently of the fact that all of them are benign and transient, the transient infant movements should be differentiated from Fejerman syndrome. Home video and video-EEG recordings are fundamental to differentiate the type of motor phenomena from those of Fejerman syndrome and from epileptic events. On the other hand, we are studying a group of patients similar to those evaluated by Fernandez Alvarez and Piscitello and colleagues to confirm the existence of transient infant movements and to propose a more precise term to define this entity.

Sandifer syndrome is the syndrome of gastroesophageal reflux associated with head-cocking, or torticollis, and abnormal dystonic posturing of the body, including opisthotonus (09). There may be associated eye and limb movements. These spells, particularly the opisthotonic posturing, may be mistaken for spasms (23; 31). Historical features can help establish the diagnosis, although not all babies with reflux will exhibit obvious signs, such as vomiting, failure to thrive, and respiratory symptoms. Spells often occur in relation to feeding. EEG is normal. Barium esophagogram, esophagoscopy, or pH probe may demonstrate the reflux.

Benign myoclonic epilepsy of infancy is another epilepsy syndrome with similar age at onset (30). However, the seizures are brief myoclonic jerks, each lasting less than 100 ms. The interictal EEG in benign myoclonic epilepsy of infancy is usually normal, but seizures are associated with bursts of polyspike-and-wave discharges. The EEG of Fejerman syndrome, both interictal and during the episodes, is always normal (11; 03).

Epileptic spasms mainly in clusters without hypsarrhythmia but also isolated should also be taken into account in the differential diagnosis. The EEG of Fejerman syndrome is also always normal interictally and during the spasms (11; 03). According to the different motor manifestations, the differential diagnoses of Fejerman syndrome are shown in Table 1 (06; 04; 03; 28; 02).

The importance of the differential diagnosis, particularly between Fejerman syndrome and epileptic infantile spasms, has been emphasized by Ghossein and Pohl (20).

Table 1. Differential Diagnosis of Benign Myoclonus of Early Infancy

Other nonepileptic conditions

	• Hyperekplexia
	• Sandifer syndrome
	• Tonic reflex seizures of early infancy
	• Adverse reactions or intolerance to exogenous agents (monosodium glutamate, metoclopramide, etc.)
	• Upward gaze deviation syndrome
	• Paroxysmal torticollis
	• Paroxysmal dystonia or choreoathetosis (paroxysmal torticollis, kinesigenic paroxysmal choreoathetosis, benign infantile dystonia)

Epileptic syndromes

	• Benign familial and nonfamilial infantile seizures
	• Infantile spasms without hypsarrhythmia
	• West syndrome
	• Myoclonic epilepsy in infancy
	• Symptomatic epileptic syndromes with tonic or myoclonic seizures

Diagnostic workup

Laboratory findings in the reported cases of Fejerman syndrome have been normal. Brain imaging has also been normal (13; 11; 27). EEGs, including interictal awake and asleep recordings as well as EEGs recorded during the motor manifestations, are always normal (03). Video-EEG monitoring facilitates rapid diagnosis (27).

The ictal polygraphic-EEG recordings during the motor manifestations show the neurophysiological features characterized by normal EEG recordings associated with myoclonus, brief tonic seizures or spasms attacks, shuddering or atonic events (03).

Management

There is no convincing evidence of any beneficial drug treatment. Antiepileptic drugs are unnecessary and potentially harmful (27). The spells resolve spontaneously. Parents may require reassurance (03).